vaccination against influenza poland,

Bull. Org. mond. Sante: 1959, 20, 333-353Bull. Wid Hith Org.

VACCINATION AGAINST INFLUENZA IN POLAND,1953-56

FELIX PRZESMYCKIDirector, State Institute of Hygiene;

Director, Department of Virology, State Institute of Hygiene,Warsaw, Poland

LEON SAWICKIHead of Laboratory, Department of Epidemiology,

State Institute of Hygiene;Senior Assistant, Department of Epidemiology,

Academy of Medicine, Warsaw, Poland

HALINA DOBROWOLSKAHead of Laboratory, Department of Virology,State Institiute of Hygiene, Warsaw, Poland

SYNOPSIS

The authors describe the methods, organization and results offour large-scale trials of polyvalent, intranasal influenza vaccine con-ducted in Poland between 1953 and 1957. Vaccination was carriedout mainly in industrial establishments, workers' and students'hostels and schools. Very few post-vaccination reactions were seen.

In these trials, the formalinized intranasal vaccine, which has theadvantage of being easy to administer, gave results not greatlydifferent from those obtained in other countries with injectedvaccines or with intranasal live-virus vaccine. The inclusion in thevaccine of a large number of strains, thus giving a broad antigenicspectrum, made it possible to obviate the difficulties involved inisolating a " precursor " strain, and thus made for quicker and moreabundant vaccine production before an epidemic.

The preliminary work on vaccination against influenza in Poland wasbegun by the State Institute of Hygiene in 1951. A test sample of formal-inized vaccine, containing strain PR8 adsorbed on phosphates, and avaccine concentrated by adsorption-elution on chicken red blood cellswere prepared. The vaccines were tested first on mice by intraperitoneal orintranasal immunization and intranasal challenge, and these experimentsrevealed a satisfactory protective power. A group of volunteers (92 people),consisting mainly of medical students in Lodz and workers of the Instituteof Hygiene, were later immunized subcutaneously with the phosphatevaccine. Investigations were carried out among a number of the peoplevaccinated to determine the post-vaccination increase in antibodies; the

- 333747

F. PRZESMYCKI, L. SAWICKI & H. DOBROWOLSKA

complement-fixation test was used. A decisive increase in post-vaccinationantibodies against the homologous strain was noted and to a certain degreeagainst strain B, which was not contained in the vaccine. Another group(52 students of the medical school) were immunized with the eluate vaccineintranasally with a special sprayer; serological investigation showed apost-vaccination increase in antibodies. However, there was a lower levelof antibodies in those vaccinated intranasally than in those vaccinatedsubcutaneously, although those immunized intranasally retained a satis-factory level for a longer period of time. Both the subcutaneous and theintranasal vaccine caused only a mild post-vaccination reaction. Theepidemiological effectiveness of the vaccine could not be established asthere was no epidemic at the time (Przesmycki & Walkowska).

The production of the vaccine on a large scale was begun in 1953 along,with preparations for an investigation among larger groups of people.

Preparation and Testing of Vaccine

Two types of vaccine were prepared from allantoic fluid of infectedchicken-embryo, in which the virus was killed with formalin: (a) concen-trated by adsorption-elution on chicken red blood cells, (b) adsorded onaluminium hydroxide. The antigenic composition of the vaccine changedyearly and will be given with each experiment discussed. The vaccine wastested in the following manner:

1. Haemagglutination titre determination;2. Haemagglutination-inhibition test with specific rat sera corresponding

to the virus strain contained in the vaccine;3. Complement-fixation test using the vaccine as antigen and standard

immune sera;4. Electron microscopy;5. Testing the vaccine on chicken-embryo for the possible presence of

live virus;6. Testing the toxic properties of the vaccine on mice;7. Testing for sterility in the usual manner;8. Determining the antigenic properties of the vaccine on rats by two

intraperitoneal injections of 1 ml of the vaccine given one week apart.Seven days after the second injection, the concentration of antibodies inthe rat sera corresponding to the strains used for the preparation of thevaccine was determined by the haemagglutination-inhibition and comple-ment-fixation tests;

9. Testing the final concentration of formalin.The aluminium hydroxide vaccine was tested by methods 5-9 above.

334

VACCINATION AGAINST INFLUENZA IN POLAND, 1953-56

Vaccine Administration

The vaccine was administered intranasally by a special glass sprayingapparatus producing a fine suspension. The apparatus was so designed asto permnit introducing into the nose a sufficiently accurate amount of thevaccine. The vaccination coasisted of spraying 0.5 ml of the vaccine intra-nasally twice at 7-10 days' interval.

Organization of Vaccination Trials

Special groups of final-year medical students or young doctors conductedthe vaccination. The groups were instructed in the methods of vaccinationand the problems connected with the etiology, clinical course and epide-miology of influenza. The groups organized and carried out the vaccinationand then followed through with observations of incidence among thevaccinated and an unvaccinated control group. Various industrial plants,elementary schools (children from age 8), student nurses, student hostels,large offices and stores were included in the vaccination. Because it wasdifficult to observe the incidence among such a large group of people(I0000 to 150000), a number of establishments were chosen for " strictobservation ". The vaccinators visited those who had fallen ill in thislatter group to verify influenza on the basis of a clinical observation and todrawn up a schematic case-history of the illness. Those who had fallen illin the remaining establishments were noted from the registers of absenteeismcaused by influenza. General supervision over the vaccination trial in thevarious areas was ensured by the public health laboratories in the givenareas.

As a result of experience, the organization of the vaccination was lateramended. The division of the vaccinated group into those " strictly observed "and those " controlled on the basis of absenteeism " was given up in 1955,because the practical efficiency of this system was found to be too lowrelative to the amount of work required. A file system was then introducedfor all workers of a given establishment-those vaccinated as well as thoseunvaccinated (this information being noted on each card)-and a closerecord kept of all who had received medical leave for clinical influenza.Every four weeks the employment figures of the factory were checked andthe files amended accordingly. A statistical evaluation of the efficacy of thevaccination (during the first experiment) was carried out with the help of thePearson coefficient. In the course of the first investigation this coefficient,calculated for the different centres, was sufficiently great, and the chancesof the correlation between " vaccinated twice " and " did not fall ill " beingjust incidental were very small (P<0.0001). In the next experiments theformula for the standard error deviation was used, accepting as statistically

335

336 F. PRZESMYCKI, L. SAWICKI & H. DOBROWOLSKA

significant the difference in incidence greater than the double standarderror deviation (D>2SE).

First Experiment

This was conducted in Lodz in 1953-54. The vaccination was basicallycompleted during November-December 1953, and schoolchildren werealready vaccinated when the influenza epidemic broke out between 11 and19 January 1954. The observation started two weeks after the completionof the vaccination and continued to 1 May 1954.

The vaccine was prepared from the following strains:

PR8 (London, 1934)A . . . i R (Warsaw, 1949)

Shklyaver (Moscow, 1947)

Al . Pan (Moscow, 1952)Czechoslovakia (Bratislava, 1947)

Only the eluate vaccine, which had a haemagglutination titre pf from1: 1280 to 1: 5120, was used.

Vaccination was chiefly carried out in student hostels and schools.A total of 54 172 people were vaccinated twice; 10 126 vaccinated

persons and a control group of 3064 unvaccinated persons were placed

TABLE 1. VACCINATION RESULTS IN L6DZ AND KATOWICEIN FIRST EXPERIMENT

No vacnae

Vaccinated twice Vaccinated once Not varcinatedCity and (control__ ____grouInep)

establishment Indexnumber cases rate number cases

rate number cases rate.~~~~~~~~~~~~~~~N

L6di:

Students' hostels 2838 42 1.47 321 8 2.59 363 23 6.33 4.3

Schools vacci-nated beforeonset of epidemic 2074 98 4.72 286 11 3.84 944 101 10.69 2.2

L6di:

Schools vacci-nated duringepidemic 719 49 6.81 340 37 10.88 305 57 18.68 2.7

Katowice:

Workers' hostel 3548 79 2.22 1452 98 6.75 3.04

* Ratio of rate among unvaccinated to rate among vaccinated.


under " strict observation " for establishing the efficacy of the vaccination.Of those vaccinated, 86.5% showed no post-vaccination reaction, 10.1%a mild reaction, 2.8 % a medium reaction, and 0.3 % a strong reaction. Amild reaction was characterized by slight rhinitis without a general reaction;a medium reaction by rhinitis, sore throat, a slight headache and a tempe-rature not exceeding 37.5°C and lasting no more than three days; and astrong reaction by an illness resembling influenza, with a typical infectionof the upper respiratory tract, headache and a temperature not higher than380C.

Sera were taken from 308 of those vaccinated, before and 10 days aftervaccination, to determine the presence of post-vaccination antibodies bythe haemagglutination-inhibition and complement-fixation tests.

There was an increase of antibodies against A and Al strains in about65% of the sera; and despite the absence of strain B in the vaccine, therewas an increase in B antibodies in 25 % of the sera examined.

The epidemiological evaluation of the efficacy of this vaccination tookplace at a time when there was an intense country-wide influenza epidemic,during which twelve Al strains were isolated, corresponding in all respectsto the Pan strain contained in the vaccine (Przesmycki et al., 1954a). Theresults of the vaccination are presented in Table 1. During this experiment,a comparison was made of the incidence in the establishments where peoplehad been vaccinated with that in similar establishments in the same citywhere people had not been vaccinated.

The decrease in incidence among those people vaccinated (as againstthe unvaccinated) was of the order of 2.2 to 4.3 times (Przesmycki et al.,1 954b).

Second Experiment

The second experiment was conducted in 1954-55. Vaccination wascarried out in October-November 1954, and observation of incidencelasted until 1 May 1955. A total of 145 005 people in four cities werevaccinated twice-12 446 in Warsaw, 89 510 in Lodz, 24 826 in Krakowand 18 223 in Gdahsk. The efficacy of the vaccination was evaluated in57 086 people. The composition of the vaccine used was the following:

A . . . Zys (Warsaw, 1953)Pan (Moscow, 1952)

Al . . . L5 (1.6di, 1954)L6 (Lodi, 1954)

B Kri (Moscow, 1949)|Bratislava (1949)

Two methods of vaccine preparation were used: concentration byadsorption and elution on chicken red blood cells, and adsorption onaluminium hydroxide.

337


TABLE 2. POST-VACCINATION ANTIBODY INCREASE IN FOUR CITIESIN SECOND EXPERIMENT

Percentage of sera showing post-vaccination titre increaseNumber

City Vaccine of paired A antigen Al antigen B antigenra

tested 2-fold >4-fold 2-fold >4-fold 2-fold >4-foldincrease increase increase increase increase increase

Eluate 367 10.62 2.98 22.61 10.33 9.80 9.79

Warsaw

Aluminium 65 18.46 4.60 18.46 26.15 7.69 21.53hydroxide

Eluate 213 60.04 15.49 48.83 26.75 39.9 46.4

L6diAluminium 158 67.08 9.49 52.53 26.91 56.96 27.84hydroxide

Eluate 280 15.0 - 17.50 0.71 26.42 4.27

da 8isk

Aluminium 166 5.42 0.60 8.43 - 12.65 1.2hydroxide

Eluate andKrakow Aluminium 315 35.0 8.6 33.8 9.6 33.5 6.2

hydroxide

The haemagglutination titre of the eluate vaccine varied from 1: 980to 1: 2560. Post-vaccination reactions were observed in 5658 people.A lack of reaction after the first inoculation in the different cities wasnoted in 84.8%-100% and after the second inoculation in 80.4%-96.4%.After the first inoculation, mild reactions varied from 2.4% to 12.2%,medium reactions from 0 to 4.1 % and strong reactions from 0 to 1.20%.After the second inoculation, mild reactions ranged from 0 to 11 %, mediumfrom 0 to 9 % and severe from 0 to 2.1 %. The percentages given are extremefigures; the overwhelming majority of reactions were concentrated aroundthe lowest figures quoted. Investigation of the post-vaccination antibodyincrease was carried out by the complement-fixation test, which was per-formed on paired sera taken from 1564 people in four cities. The post-vaccination antibody increase fluctuated fairly widely in the different cities.The detailed results of this study are given in Table 2.

The epidemiological evaluation of the vaccination was conducted duringa country-wide B epidemic which spread in March and April of 1955.During this epidemic, six B strains were isolated from material gathered infour cities (Przesmycki et al., 1956). These strains corresponded in antigenicstructure to the B strains contained in the vaccine. The results are given inTables 3, 4 and 5 and in Fig. 1 and 2.

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VACCINATION AGAINST INFLUENZA IN POLAND, 1953-56 341

TABLE 5. VACCINATION RESULTS IN KRAKOW IN SECOND EXPERIMENT

Vaccinated twice(eluate and Not vaccinated

aluminium hydroxide) IndexKrakowIne

number cases morbidity number cases morbidityrate (%) rate (%

Strict observation

Nurses' schools 664 49 7.3 113 15 13.2 1.8 (-)

Primary schools 1701 39 2.3 669 24 3.6 1.5 (-)

Industrial 2697 183 6.16 3752 307 8.18 1.3 (±)establishments

Stores and offices 893 21 2.35 1394 154 11.05 4.8 (+)

Observation of basis of absenteeism

Primary schools 3529 891 25.25 326 145 44.48 1.7 (+)

Offices 2368 154 6.50 2267 268 11.22 1.8 (+)

Industrialestablishment,s 2360 162 6.8 5963 442 7.4 1.0 (±)

* The index is the ratio of the morbidity rate among the unvaccinated to the rate among thevaccinated. The sign (+) indicates statistical significance (D>2SE), while (-) indicates thatthe index is not statistically significant (D<2SE).

FIG. 1. INFLUENZA MORBIDITY IN 7 TEXTILE FACTORIES UNDERSTRICT OBSERVATION IN L61D2: SECOND EXPERIMENT *

1.0 1.0

I'

/nocnto,

0.5 n v 0.5

January February March AprilI1955

.-UnvaccinatedVaccinated

*Number vaccinated: 4271; total morbidity rate: 1.7%.Number not vaccinated: 6510; total morbidity rate: 4.5%.Ratio: 2.6

There was, on the average, a twofold decrease of incidence among thosevaccinated. A difference was noted, however, in the efficacy of the vaccina-tion among the different cities and, to a certain degree, according to the


FIG. 2. INFLUENZA MORBIDITY IN 6 TEXTILE FACTORIES IN L6DZOBSERVED ON BASIS OF ABSENTEEISM: SECOND EXPERIMENT'

1.0 I.0

0.5 /0.5

January February March April

1955WHO 8441

UnvaccinatedVaccinated

Number vaccinated: 6732; total morbidity rate: 2.1%.Number not vaccinated: 5480; total morbidity rate: 6.88%.Ratio: 3.0

type of vaccine used. Thus, in some cities, the aluminium hydroxide vaccinewas the more effective.

During this second experiment, what has been called the " inner control"system was exclusively used; by this is meant that unvaccinated groups inthe same establishments as the vaccinated were used as controls (Bilek etal., 1956; Przesmycki & Sawicki, 1956; Przesmycki, Sawicki & Dobro-wolska, 1956; Zan'ski & Stasik, 1956).

Third Experiment

The third experiment was conducted in 1955-56. Vaccination wascompleted in October-November 1955; observation continued until 1 May1956. The total number of people vaccinated twice was 129 521 in ninecities: Warsaw, 15 224; Lodz, 43 075; Krakow, 14 992; Gdan'sk, 12 765;Bialystok, 5679; Wroclaw, 7900; Poznah, 16 039; Katowice, 8123, andSzczecin, 5368. The composition of the vaccine was as follows:

A . . Zys (Warsaw, 1953)

Al . . Pan (Moscow, 1952)L5 (L6di, 1954))

B Kri (Moscow, 1949)B Hradec (Czechoslovakia, 1949)


The vaccine was prepared by two methods: concentration by adsorptionand elution on chicken red blood cells and adsorption on aluminiumhydroxide.

Changes in organization were introduced during this experiment. Vacci-nation was carried out by nurses in factory dispensaries or by school nursesunder the supervision of doctors. The city or provincial public healthlaboratories supervised the vaccination through the doctors responsible.All personnel were paid from a special fund provided by the Ministry ofHealth. Those who fell clinically ill with influenza (among both thevaccinated and the unvaccinated) in any one- factory were recorded in aspecial file embracing all the workers in that factory. All those who hadbeen given medical leave for influenza were noted in the file. The weeklynumber of cases (among the vaccinated and unvaccinated) was noted ona special index throughout the entire period of the experiment.

1955-56 was a non-epidemic season. The results obtained in thisexperiment are given in Table 6.A decrease in incidence of clinical influenza compared with the control

groups during this non-epidemic season was recorded in a number ofestablishments. This phenomenon had not been anticipated and was notimmediately understandable; it therefore required clarification through aspecial analysis of those who had fallen ill in all the establishments underobservation. It appeared that in Warsaw, Wroclaw and other localities,infections of the upper respiratory tract, identified as influenza, exceededthe non-epidemic level (Fig. 3). (In inter-epidemic periods, the official regis-tration is usually practically nil.) Among all the establishments observed(180), there were 32 (17.7%) which during the period from November 1955to March 1956 had an incidence of over 10% of the personnel. Of these32 plants with high incidence there were 25 (78.1 %) in which the incidenceamong the vaccinated showed a statistically significant reduction (see, forexample, Fig. 4 and 5).

There are not sufficient data to show conclusively that the increase inincidence observed in a number of establishments was caused by virusinfluenza, particularly as laboratory tests were not conducted. However,

- FIG. 3. INFLUENZA MORBIDITY AMONG VACCINATED PERSONS INBIALYSTOK, WROCLAW AND L6DZ: THIRD EXPERIMENT

1%0BIAtYSTOK WROCAW KIELCEX2 2

S O N D J F M A S O N DJ F M A S O N D J FM A A1955 1956 1955 1956 1955 1956

WHO 8443

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FIG. 4. INFLUENZA MORBIDITY IN A FACTORY IN WROCLAW:THIRD EXPERIMENT*

4 4

3 3'2 2~~~~~,

November December January February March1955 1956

WHO 8444

. - UnvaccinatedVaccinated

* Number vaccinated: 476; total morbidity rate: 10.92%.Number not vaccinated: 386; total morbidity rate: 36.53%.Ratio: 3.34

FIG. 5. INFLUENZA MORBIDITY IN WARSAW RADIO FACTORYTHIRD EXPERIMENT *

4 4

3 3

2 /2

December | January February March April1955 I 1956

WHO 8445

UnvoccinatedVa cc inated

Number vaccinated: 1600; total morbidity rate: 7.31%.Number not vaccinated: 1500; total morbidity rate: 24.73%.Ratio: 3.3

since the increase in upper respiratory infections was very marked and theclinical and epidemiological features resembled influenza very closely, onecan say with some probability that the local epidemics were a sort of"' precursor " of the epidemic which appeared in Poland later (March 1957)and were caused by a virus closely related to A/Netherlands/36/56. (It


FIG. 6. INFLUENZA MORBIDITY IN KRAKOW CLOTHING FACTORY:THIRD EXPERIMENT *

UnvaccinatedVocci noted

* Number vaccinated: 384; total morbidity rate: 6.35%.Number not vaccinated: 265; total morbidity rate: 12.83%.Ratio: 2

FIG. 7. INFLUENZA MORBIDITY IN WARSAW WORKERS' HOSTELS:THIRD AND FOURTH EXPERIMENTS *

December January February March1955 1956

December January February March April1956 1957

WHO 8447

-____ UnvoccinatedVaccinated

* Upper graph:Number vaccinated: 1540; total morbidity rate: 0.84%.Number not vaccinated: 1260; total morbidity rate: 2.22%.Ratio: 2.64

Lower graph:Number vaccinated: 1558; total morbidity rate: 0.64%.Number not vaccinated: 627; total morbidity rate: 5.42%.Ratio: 9.0

347

22

January February March1956

*HO 8446


should be noted that epidemics caused by this virus had already appearedin some other parts of Europe at the beginning of 1956.) A similar situationwas noted in Poland in 1953-54. The mild epidemic in May 1953 was theprecursor of the country-wide epidemic in January 1954 and was causedby the same strains (Sawicki, 1956a, 1956b). In relation to the situationin 1956, however, the necessary laboratory confirmation of a similar phe-nomenon is lacking. Nevertheless, it does seem that in a significant numberof cases, the efficacy of the vaccination was in fact shown in certainfactories during the local epidemics (e.g., in the radio factory in Warsawthere was an incidence of 16.4% among those unvaccinated as comparedwith 4.30% among those vaccinated). In a number of establishments,however, there was a statistically significant decrease of incidence amongthose vaccinated as compared with the controls in spite of a lack of in-crease of influenza registered in the establishments (Fig. 6 and 7).

It appears that the method of summarizing the cases of influenza duringthe entire period of observation regardless of the dynamics of incidence isunacceptable; it allows for the influence of many accidental factors, espe-cially in the period between epidemics when the percentage of virus influenzaamong cases stated to be influenza is barely perceptible. The conclusion isdrawn therefrom that the efficacy of vaccination can only be evaluatedduring a clear epidemic (even though local) in a given establishment(L. Sawicki - unpublished data).

Fourth Experiment

The fourth experiment was conducted in 1956-57. Vaccination tookplace in November-December 1956, and observation lasted to 1 May 1957.A total of 55 450 people in four cities were vaccinated twice: Warsaw,12 962; Lodz, 24 219; Poznan', 6593; and Gdansk, 11 676. The compositionof the vaccine was as follows:

A . . . Zys (Warsaw, 1953)Pan (Moscow, 1952)

Al . . . FM1 (London, 1947)L5 (L6di, 1954)

B . . . Kri (Moscow, 1949)

The aluminium hydroxide vaccine was used exclusively. The methodof testing the vaccine was the same as in the former experiments, and thesystem of organization the same as in the third experiment.

The epidemiological efficacy of the vaccination was evaluated duringthe influenza epidemic which appeared in March-April of 1957 and wascaused by a virus closely related to A/Netherlands/3/56 (L. Mietkiewicz-

348


unpublished data). Five strains of this kind were isolated in Poland. Astatistically significant decrease of incidence among those vaccinated wasseen in 40 of the 62 establishments observed. Those vaccinated in theseestablishments amounted to 72.2% of the total number of persons vaccinatedthroughout Poland. Only the incidence noted during a significant increasein the number of registrations in a given establishment was taken intoconsideration in evaluating the efficacy of vaccination. Incidence amongthose vaccinated was 1.5 to 3.4 times less than among those not vaccinated.It was shown in this experiment that the vaccine was effective even thoughit did not contain strain A/Netherlands/36/56. It should be mentioned,however, that in general the efficacy in this trial was less marked than inprevious experiments, although it was clear-cut in some establishments(Fig. 8 and 9).

The results of vaccination are presented in Table 7.

FIG. 8. INFLUENZA MORBIDITY IN L61DZ TEXTILE FACTORY:FOURTH EXPERIMENT *

.------ Unvaccinated

Va cci nated


12 a 12

10 10

8 it

6 ~~~~~~~~~~~~~~~~~~~~~6

4 4II

2 2f tt - 0 / e _

1 956 1 1957WHO 8448

349


FIG. 9. INFLUENZA MORBIDITY IN WARSAW RADIO FACTORY:FOURTH EXPERIMENT *

l-

6

4

2

I \%I -

/-I

\ , l~IV

NovemberI December January FebruaryI MarchI A pril11956 1957

6

4

2

WHO 8449

- - UnvaccinatedVaccinated


TABLE 7. VACCINATION RESULTS IN FOUR CITIES IN FOURTH EXPERIMENT

Vaccinated twice Not vaccinatedCity and (aluminium hydroxide) Ntvciae

establishment Index *number cases morbidity number cases morbidity

rate %)rate (%)

Warsaw:

18 industrialestablishments 12 962 763 5.80 23 541 3 009 12.70 2.1 (l)

L6di:

27 industrialestablishments 24 219 2194 9.05 22 987 3 251 14.10 1.5 (+)

Poznan:

7 industrialestablishments 6 593 465 7.05 17 505 1 807 10.32 1.4 (+)

Primary schools 1 260 188 14.92 1 524 425 27.89 1.8 (+)

Gdaiisk:

10 industrialestablishments 11676 566 4.85 8 157 624 7.60 1.5 (t)

* The index is the ratio of the morbidity rate among the unvaccinated to the rate among thevaccinated. The sign (+) indicates statistical significance (D>2SE).

350


Discussion

This paper presents the results of four years' investigations on theefficacy of formalinized vaccine administered intranasally. In three experi-ments two types of vaccine were used (eluate and aluminium hydroxide);in the fourth experiment only the aluminium hydroxide vaccine was used,since no tangible differences were noted between the two and the aluminiumhydroxide vaccine is substantially cheaper and easier to prepare. Thevaccine gave rise to very few post-vaccination reactions-rather less than1 %, as confirmed during the first two experiments among 12 471 personsvaccinated.

Analysing the results of vaccination, it is necessary to note that thebest results were achieved during the first experiment. The epidemic brokeout immediately after the completion of vaccination and in some establish-ments during vaccination. There was a definite reduction of incidenceamong children vaccinated during the epidemic. This could be interpretedby the interference phenomenon. The vaccine used during this experimentcontained strain Al (Pan), completely similar in its antigenic structure tothe strain which caused the epidemic. These strains are quite similar toA/England/l/53.

The efficacy of vaccination during the second experiment was evaluatedduring a B epidemic of a predominantly focal character. The efficacy ofvaccination varied quite extensively in the different establishments, theindex of the reduction of incidence among those vaccinated ranging ingeneral from 1.7 to 2.9 and in some establishments reaching 8.0. Thestrains identified during this epidemic partly corresponded to the classicalLee strain. The vaccine contained strain B/Kri/Moscow/47, very similarto Lee, and strain B/Bratislava/49.

The third experiment was most difficult to interpret since the efficacyof the vaccine was evaluated in an inter-epidemic season. A summarycomparison of incidence among vaccinated and unvaccinated for the entireperiod of observation revealed in many establishments a statisticallysignificant reduction of incidence among those vaccinated. A thoroughanalysis of incidence carried out in all establishments showed a seasonalincrease of illness in some cities and industrial plants which was consideredto be influenza. It is possible that during this period, which for the countryas a whole was an inter-epidemic one, there were local influenza foci inwhich the previous vaccination was still effective and contributed to reducethe incidence. These foci may have been the precursors of the epidemicwhich broke out in March 1957.

In the fourth experiment a reduction of incidence among those vaccinatedwas achieved, of an order of from 1.5 to 3.4. The strains included inthe vaccine were selected in order to achieve a broad antigenic spectrum.

351


The vaccine did not contain strain A/Netherlands/36/56, which was notavailable when the vaccine was being prepared. Perhaps the efficacy ofthe vaccine can be attributed to the fact that strains Pan and L5 (similar toA/England/1/53) included in the vaccine share some antigenic componentswith A/Netherlands/36/56.

In general, the efficacy of vaccination achieved by using a polyvalent,formalinized, intranasal vaccine is not much different from that obtainedwith influenza vaccination in other countries. The use by the Polish StateInstitute of Hygiene of a greater number of strains giving a broad anti-genic spectrum seems to have made it possible to avoid the difficultiesinvolved in isolating a precursor strain in order to include it in the vaccine.In practice this allowed for the production of a greater amount of vaccinebefore an epidemic.

It also appears that the value of the vaccine described and of the methodof vaccination lies in the simplicity of application and the practicallynegligible post-vaccination reactions.

In order to determine the increase in post-vaccination antibodies,2160 paired serum samples of vaccinated persons were analysed during thefirst and second experiments, but the results were not uniform, the antibodyincrease varying extensively and being different in different cities. Attimes differences connected with the type of vaccine were also noted. Moststriking is the lack of parallel between the antigenic and protective powerof the vaccine, which was revealed on an extensive scale in a number ofepidemiological investigations. The possibility cannot be excluded thatthe immunizing mechanism of the intranasal vaccine is based to a consider-able degree on local immunity phenomena of the upper respiratory tractinduced by the vaccine. This hypothesis requires affirmation in a specialinvestigation.

RIASUME

Un vaccin antigrippal, formole et concentre, a ete appliqu6 par voie intranasale,au cours de quatre annees. a des groupes importants d'ouvriers et d'ecoliers. Les resultatsde ces essais, les methodes de production, de contr6le et d'application du vaccin sontdecrits dans cet article.

Les vaccins contenaient en regle generale, 5-6 souches de virus A, Al et B. Ils etaientconcentres par adsorption-elution ou adsorb6s sur hydroxyde d'aluminium, et adminis-tres par voie intranasale deux fois, a une semaine d'intervalle, au moyen de pulverisateursen verre.

Le vaccin a provoque moins de 1% de reactions vaccinales parmi 12 471 sujetsvaccines. Lors des premiers essais, 54 172 personnes ont e vaccinees deux fois. Lafrequence de la grippe parmi les vaccines, determinee au cours d'une epidemie A virus Al,qui en 1954 a affecte l'ensemble du pays, a e reduite de facon significative (indice dereduction 2,2-4,5). Durant la deuxieme experience, au cours d'une epidemie B en 1955,on observa une diminution de moitie de la frequence des cas declares parmi 145 000 per-sonnes vaccinees, dans quatre villes. L'efficacit6 tres nette de la troisieme vaccination ae observee au cours d'une periode interepidemique en 1956, dans un certain nombre

352

VACCINATION AGAINST INFLUENZA IN POLAND, 1953-56 353

d'usines, oui ont &late des poussees d'infections respiratoires aigues. Ces foyers etaientprobablement les precurseurs d'une epidemie causee par un virus apparente a A/Nether-lands/36/56. L'epidemie de 1957, causee par ce virus, a e l'occasion d'une quatriemeexperience. Au total 55 450 personnes ont ete vaccinees dans quatre villes. Le vaccin necontenait pas le virus Netherlands/36/56, mais plusieurs autres ayant avec lui des anti-genes communs. La reduction de la frequence a e moindre que dans les pr&edentsessais; l'indice de reduction a oscill autour de 2.

Lors des deux premi6res experiences, l'accroissement du taux des anticorps a everifie. II variait entre de larges limites et aucun parallelisme n'a pu etre etabli entre lepouvoir antigenique du vaccin et son efficacite epidemiologique.

REFERENCES

Bilek, M. et al. (1956) Przegl. epidem., 2, 121Przesmycki, F., & Sawicki, L. (1956) Bull. Acad. pol. Sci. Cl. 2, 4, 141Przesmycki, F., Sawicki, L. & Dobrowolska, H. (1956) Przegl. epidem., 2, 128Przesmycki, F. & Walkowska, E. (1951) Med. dosw. Mikrobiol., 1, 1Przesmycki, F. et al. (1954a) Med. dosw. Mikrobiol., 3, 241Przesmycki, F. et al. (1954b) Med. dogw. Mikrobiol., 4, 346Przesmycki, F. et al. (1956) Przegl. epidem., 2, 97Sawicki, L. (1956a) Bull. Acad. pol. Sci. Cl. 2, 3, 115Sawicki, L. (1956b) Przegl. epidem., 2, 103Zaiiski, J. & Stasik, M. (1956) Przegl. epidem., 2, 117

vaccination against influenza poland,

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